Abstract
Genes regulated by cooperating oncogenes enhance leukemia stem cell growth and survival.
Major finding: Genes regulated by cooperating oncogenes enhance leukemia stem cell growth and survival.
Approach: CRGs were identified in mouse primitive leukemia cells and extended to human leukemia samples.
Impact: The CRG signature can be used to discover compounds that may selectively target leukemic cells.
Malignant transformation involves multiple oncogenic events that cooperatively modulate the expression of downstream cooperation response genes (CRG) involved in tumorigenesis. To investigate the contribution of CRGs in leukemia stem cell (LSC) biology, Ashton and colleagues used a mouse model of blast crisis chronic myelogenous leukemia driven by expression of the BCR-ABL and NUP98-HOXA9 oncogenic fusion proteins. Transcriptional profiling of primitive leukemia stem/progenitor cells isolated from these mice identified 72 CRGs that were synergistically dysregulated in the presence of both oncogenes. Importantly, this CRG signature was also partially conserved in primary human BCR-ABL+ leukemia patient samples, in which 13 CRGs showed a similar pattern of aberrant expression. Many of the upregulated CRGs were functionally important in leukemia pathogenesis in vivo, as engraftment of leukemia cells in transplant recipient mice was diminished upon downregulation in a targeted short hairpin RNA (shRNA) library screen. These results were further validated for 6 genes that regulate tumor cell interactions with the microenvironment, including SerpinB2, which induced the greatest impairment of leukemia cell engraftment upon shRNA-mediated knockdown. Moreover, SerpinB2 deficiency resulted in a reduced frequency of LSCs but did not affect normal hematopoietic cell function, suggesting that this protein specifically regulates LSC survival. Given the role of CRGs in promoting LSC growth, this gene set was used to query a connectivity map database to predict compounds that would efficiently target leukemia cells. Indeed, several of the identified agents, including tyrophostin AG825 and 4-hydroxynonenal, were selectively cytotoxic to primary mouse and human leukemia cells and abrogated leukemia progenitor cell function in colony formation assays. These findings indicate that genes induced by oncogenic cooperativity are essential for leukemic transformation and suggest that analysis of CRGs may be useful in developing improved antileukemia therapies.
